Circadian rhythms are important cellular pathways first described for their essential role in helping organisms adjust to the 24 h day-night cycle and synchronize physiological and behavioral functions. Most organisms have evolved a circadian central clock to anticipate daily environmental changes in light, temperature, and mate availability. It is now understood that multiple clocks exist in organisms to regulate the functions of specific organs. Epidemiological studies in humans reported that disruption of the circadian rhythms caused by sleep deprivation is linked to the onset of immune-related conditions, suggesting the importance of circadian regulation of immunity. Mechanistic studies to define how circadian clocks and immune responses interact have profound implications for human health. However, elucidating the clocks and their tissue-specific functions has been challenging in mammals. Many studies using simple model organisms such ashave been pioneering in discovering that the clock controls innate immune responses and immune challenges can impact circadian rhythms and/or their outcomes. In this review, we will report genetic studies using the humble fruit fly that identified the existence of reciprocal interactions between the circadian pathway and innate immune signaling, contributing to elucidate mechanisms in the growing field of chrono-immunology. Drosophila melanogaster
